This invention relates to the use of certain transdermal flux enhancers in combination with iontophoresis for the topical administration of pharmaceutical agents.
Many pharmaceutical agents are ionized. As a result, in conventional topical drug delivery systems, they are unable to adequately penetrate the skin surface, and so do not reach the desired site of action at therapeutic concentrations. With such ionic drugs, this problem has been partially solved by the process of iontophoresis. By this means, it has been possible to enhance the localized delivery of drug to tissue (e.g., dermis, muscle, bone joints, and the like) which is at or near the site of application. By this means, it has also been possible to transport the drug into the blood stream, thus providing systemic delivery of drug to the entire body.
According to the process of iontophoresis, an electric potential is applied across a localized portion of body tissue as a drug containing solution is held against the skin in that localized area. Sufficient potential is applied so as to cause a small current to pass through the solution and the adjacent body tissue. In this manner, the drug is "phoresed" from the solution across the dermal barrier and into the local tissue (to produce high local tissue levels of the drug), or given enough time and other appropriate conditions, into the blood stream, whereby the drug is delivered systemically to more remote site(s) of action. For a review of iontophoresis and iontophoretic devices, see Tyle, Pharm. Res., v. 3, pp. 318-326 (1986).
More recently, it has been shown in studies using mannitol that the flux of neutral, polar molecules is enhanced by iontophoresis, particularly in the presence of a cation such as Na.sup.+, Burnette et al., J. Pharm. Sci., v. 75, pp. 738-743 (1986). See also Meyer et al., Am. J. Med. Sci., v. 296, pp. 321-324 (1989). Thus the flux of a pharmaceutical agent which is not ionized or even capable of ionization can also be increased by the local application of an electric potential.
In the topical administration of pharmaceutical agents, iontophoresis is primarily limited by two interrelated factors: (1) Transport through the skin generally occurs via appendages (e.g., hair follicles, sweat glands, etc.) or small "pores", which represent only a fraction of the total skin surface area. Consequently, these pathways are exposed to a very high charge density relative to the total applied current, leading to irreversible changes or damage. (2) Since the rate of drug delivery is proportional to the applied current, the magnitude of delivery is severely limited by the problem described in (1) above.
As an alternative method for enhancing the transdermal flux of pharmaceutical agents, a variety of so-called penetration enhancers have been proposed for use as adjuncts in the topical administration of pharmaceutical agents. For example, see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616, 4,537,776, 4,557,934; Stoughton, Arch. Derm. v. 118, pp. 474-477 (1982); Cooper, J. Pharm. Sci., v. 73, pp. 1153-1156 (1984); and Akhtesi et al., J. Pharm. Pharmacol. v. 36, p. 7P (1984).
Surprisingly, we have now found that the combination of iontophoresis with such transdermal flux enhancing agents leads to a synergistic effect in which flux across the dermal barrier is much higher than expected. This permits local and systemic delivery of a given amount of pharmaceutical agents by iontophoresis under much milder conditions of electrical potential and current density, avoiding the irreversible changes or damage to the skin noted above.